U.S. patent number 7,973,063 [Application Number 12/588,267] was granted by the patent office on 2011-07-05 for methods for activating ppar gamma-type receptors.
This patent grant is currently assigned to Galderma Research & Development. Invention is credited to Jerome Aubert, Jean-Guy Boiteau, Laurence Clary, Pascale Mauvais, Michel Rivier, Etienne Thoreau.
United States Patent |
7,973,063 |
Aubert , et al. |
July 5, 2011 |
Methods for activating PPAR gamma-type receptors
Abstract
Novel biaromatic compounds having the following structural
formula (I): ##STR00001## are formulated into pharmaceutical
compositions suited for administration in human or veterinary
medicine, in particular in dermatology as well as in the fields of
cardiovascular diseases, immune diseases and/or diseases related to
the metabolism of lipids, or, alternatively, into cosmetic
compositions.
Inventors: |
Aubert; Jerome (Grasse,
FR), Clary; Laurence (La Colle sur Loup,
FR), Mauvais; Pascale (Antibes, FR),
Rivier; Michel (Nice, FR), Thoreau; Etienne
(Saint Vallier de Thiey, FR), Boiteau; Jean-Guy
(Saint Aunes, FR) |
Assignee: |
Galderma Research &
Development (Biot, FR)
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Family
ID: |
34968619 |
Appl.
No.: |
12/588,267 |
Filed: |
October 9, 2009 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100035988 A1 |
Feb 11, 2010 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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11592276 |
Nov 3, 2006 |
7626054 |
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PCT/EP2005/005797 |
Apr 29, 2005 |
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60574217 |
May 26, 2004 |
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Foreign Application Priority Data
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May 6, 2004 [FR] |
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04 04913 |
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Current U.S.
Class: |
514/369; 562/433;
562/439; 562/405; 560/34; 560/19 |
Current CPC
Class: |
C07C
275/42 (20130101); A61P 17/10 (20180101); C07C
2601/14 (20170501); C07C 2601/02 (20170501); C07C
2601/08 (20170501) |
Current International
Class: |
A61K
31/425 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 0212210 |
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Feb 2002 |
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WO |
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WO 2004048351 |
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Jun 2004 |
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WO |
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Other References
International Search Report for corresponding PCT/EP2005/005797
dated Jul. 21, 2005, 3 pages. cited by other .
STN Caplus Abstract, Accession No. 2004:432769, Document No.
140:429035. cited by other .
International Search Report for corresponding PCT/EP2005/005797
dated Jul. 21, 2005, 3 pages. cited by other.
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Primary Examiner: Katakam; Sudhakar
Attorney, Agent or Firm: Buchanan Ingersoll & Rooney,
P.C.
Parent Case Text
CROSS-REFERENCE TO EARLIER APPLICATIONS
This application is a divisional of U.S. patent application Ser.
No. 11/592,276 filed Nov. 3, 2006, which is a continuation of
PCT/EP 2005/005797 filed Apr. 29, 2005 and designating the United
States, published in the English language as WO 2005/108352 A1 on
Nov. 17, 2005, which claims the benefit of U.S. Provisional
Application No. 60/574,217, filed May 26, 2004 and also claims
priority of FR04/04913, filed May 6, 2004 in France, each hereby
expressly incorporated by reference and each assigned to the
assignee hereof.
Claims
What is claimed is:
1. A method for the activation of receptors of PPAR.gamma.,
comprising contacting said receptors with an effective PPAR.gamma.
receptor-activating amount of a biaromatic compound having the
following structural formula (I): ##STR00019## in which: R1 is an
alkyl radical selected from the group consisting of methyl, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, n-pentyl,
isopentyl, n-hexyl, isohexyl, cyclohexyl, ethylenyl, allyl,
propenyl, butenyl, pentenyl and hexenyl, or an acetyl group or a
methylcyclopropane group; R2 is an alkyl radical having 3 to 8
carbon atoms; R3 is a hydrogen atom or an alkyl radical having 1 to
6 carbon atoms; R4 and R5, which are identical or different, are
each a hydrogen atom, a halogen atom, a hydroxyl radical, an alkyl
radical having from 1 to 6 carbon atoms, an alkoxy radical, a
benzyloxy radical or a trifluoromethyl radical; or an isomer,
optical or geometrical, pure or as a mixture, in any proportion, of
said compound of formula (I) or a tautomeric form, or a salt of
said compound of formula (I).
2. The method as defined by claim 1, wherein the compound having
formula (I) is in the form of an alkali metal salt or an alkaline
earth metal salt or an organic amine salt thereof.
3. The method as defined by claim 1, wherein the compound having
formula (I) is in the form of a sodium salt thereof.
4. The method as defined by claim 1, wherein the compound having
formula (I) is in the form of an amino acid salt thereof.
5. The method as defined by claim 1, wherein the compound having
formula (I) is in the form of an arginine salt or a lysine salt
thereof.
6. The method as defined by claim 1, wherein, in the compound
having formula (I), R2 is selected from the group consisting of
n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl,
n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl,
n-heptyl, isoheptyl, n-octyl, isooctyl, allyl, propenyl, butenyl,
pentenyl, hexenyl, heptenyl and octenyl radicals.
7. The method as defined by claim 1, wherein the compound having
formula (I) bears a fluorine, bromine or chlorine atom
substituent.
8. The method as defined by claim 1, wherein the compound having
formula (I) bears a methoxy, ethoxy, isopropyloxy, tert-butoxy, or
hexyloxy radical substituent.
9. The method as defined by claim 1, wherein the compound having
formula (I) is selected from the group consisting of:
2(S)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]prop-
anoic acid,
2(S)-Propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoi-
c acid,
2(S)-Cyclopropylmethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4--
yl]propanoic acid,
3-[3'-(1-Methyl-3-pentylureido)biphenyl-4-yl]-2(S)-propoxypropanoic
acid,
2(S)-Allyloxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Methoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
3-[3'-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropanoic
acid,
2(S)-Ethoxy-3-[3'-(1-methyl-3-propylureido)biphenyl-4-yl]propanoic
acid,
3-[3'-(3-Cyclopropylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethox-
ypropanoic acid,
3-[3'-(3-Cyclopentylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropa-
noic acid,
2(S)-Ethoxy-3-[3-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4--
yl]propanoic acid,
2(S)-Ethoxy-3-[4'-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propan-
oic acid,
3-[3,4'-Difluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-
-ethoxypropanoic acid, Methyl
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate,
Methyl
2(S)-cyclopropylmethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4--
yl]propanoate,
2(S)-Cyclopropylmethoxy-3-[3'-(3-cyclopropylmethyl-1-methylureido)bipheny-
l-4-yl]propanoic acid,
3-{3'-[3-(2-Cyclohexylethyl)-1-methylureido]biphenyl-4-yl}-2(S)-ethoxypro-
panoic acid,
2(R)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(R)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(R)-Allyloxy-3[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
3-[3'-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic
acid, and Allyl
3-[3'-(3-allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropano-
ate.
10. The method as defined by claim 1, wherein the compound having
formula (I) has at least one of the following characteristics: R1
is a methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl or
tert-butyl radical, or a methylcyclopropane group, R2 is a
n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl,
n-heptyl or isoheptyl radical, R3 is a hydrogen atom, R4 and/or R5
are each a hydrogen atom or a fluorine atom.
11. The method as defined by claim 1, wherein, in the compound
having formula (I), R1 is an alkyl radical selected from the group
consisting of methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl,
cyclohexyl, ethylenyl, allyl, propenyl, butenyl, pentenyl and
hexenyl.
12. The method as defined by claim 11, wherein R1 is an alkyl
radical selected from the group consisting of methyl, ethyl,
n-propyl, isopropyl, cyclopropyl, isobutyl and tert-butyl.
13. A method for the activation of receptors of PPAR.gamma.,
comprising contacting said receptors with an effective PPAR.gamma.
receptor-activating amount of a biaromatic compound having the
following structural formula (I): ##STR00020## in which: R1 is a
methyl, ethyl, propyl or allyl radical; R2 is an alkyl radical
having 3 to 8 carbon atoms; R3 is a hydrogen atom or an alkyl
radical having 1 to 6 carbon atoms; R4 and R5, which are identical
or different, are each a hydrogen atom, a halogen atom, a hydroxyl
radical, an alkyl radical having from 1 to 6 carbon atoms, an
alkoxy radical, a benzyloxy radical or a trifluoromethyl radical;
or an isomer, optical or geometrical, pure or as a mixture, in any
proportion, of said compound of formula (I) or a tautomeric form,
or a salt of said compound of formula (I).
14. The method as defined by claim 11, wherein, in the compound
having formula (I), R2 is an alkyl radical selected from the group
consisting of n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl,
cyclohexyl, n-heptyl and isoheptyl.
15. The method as defined by claim 12, wherein, in the compound
having formula (I), R2 is an alkyl radical selected from the group
consisting of n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl,
cyclohexyl, n-heptyl and isoheptyl.
16. The method as defined by claim 13, wherein, in the compound
having the formula (I), R2 is an alkyl radical selected from the
group consisting of n-pentyl, isopentyl, cyclopentyl, n-hexyl,
isohexyl, cyclohexyl, n-heptyl and isoheptyl.
17. The method as defined by claim 11, wherein, in the compound
having the formula (I), R3 is a hydrogen atom.
18. The method as defined by claim 12, wherein, in the compound
having the formula (I), R3 is a hydrogen atom.
19. The method as defined by claim 13, wherein, in the compound
having the formula (I), R3 is a hydrogen atom.
20. The method as defined by claim 11, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
21. The method as defined by claim 12, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
22. The method as defined by claim 13, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
23. The method as defined by claim 14, wherein, in the compound
having the formula (I), R3 is a hydrogen atom.
24. The method as defined by claim 15, wherein, in the compound
having the formula (I), R3 is a hydrogen atom.
25. The method as defined by claim 16, wherein, in the compound
having the formula (I), R3 is a hydrogen atom.
26. The method as defined by claim 14, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
27. The method as defined by claim 15, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
28. The method as defined by claim 16, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
29. The method as defined by claim 17, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
30. The method as defined by claim 18, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
31. The method as defined by claim 19, wherein, in the compound
having the formula (I), R4 and R5, which are identical or
different, are each a hydrogen atom or a fluorine atom.
32. The method as defined by claim 13, wherein, in the compound
having the formula (I), R1 is ethyl.
33. The method as defined by claim 30, wherein the compound having
formula (I) is
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid.
34. The method as defined by claim 13, wherein the compound having
formula (I) is selected from the group consisting of:
2(S)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoi-
c acid,
3-[3'-(1-Methyl-3-pentylureido)biphenyl-4-yl]-2(S)-propoxypropanoi-
c acid,
2(S)-Allyloxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propano-
ic acid,
2(S)-Methoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propano-
ic acid,
3-[3'-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropano-
ic acid,
2(S)-Ethoxy-3-[3'-(1-methyl-3-propylureido)biphenyl-4-yl]propanoi-
c acid,
3-[3'-(3-Cyclopropylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-etho-
xypropanoic acid,
3-[3'-(3-Cyclopentylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropa-
noic acid,
2(S)-Ethoxy-3-[3-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4--
yl]propanoic acid,
2(S)-Ethoxy-3-[4'-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propan-
oic acid,
3-[3,4'-Difluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-
-ethoxypropanoic acid, Methyl
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate,
3-{3'-[3-(2-Cyclohexylethyl)-1-methylureido]biphenyl-4-yl}-2(S)-ethoxypro-
panoic acid,
2(R)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(R)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(R)-Allyloxy-3[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
3-[3'-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic
acid, and Allyl
3-[3'-(3-allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropano-
ate.
35. A method for the activation of PPAR.gamma., comprising
contacting said receptors with an effective PPAR.gamma.
receptor-activating amount of a biaromatic compound having the
following structural formula (I): ##STR00021## in which: R1 is
methyl, ethyl, allyl, cyclopropylmethyl or benzyl; R2 is n-pentyl
or n-heptyl; R3 is hydrogen; R4 and R5, which are identical or
different, are a hydrogen atom or a fluorine atom; and the compound
has the (S) configuration at the 2-position of the propionic acid
portion of the molecule.
36. The method as defined by claim 35, wherein the compound having
formula (I) is selected from the group consisting of:
2(S)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]prop-
anoic acid,
2(S)-Benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoi-
c acid,
2(S)-Cyclopropylmethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4--
yl]propanoic acid,
2(S)-Allyloxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid,
2(S)-Benzyloxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propano-
ic acid,
2(S)-Methoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propano-
ic acid,
3-[3'-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropano-
ic acid,
2(S)-Ethoxy-3-[3-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl-
]propanoic acid,
2(S)-Ethoxy-3-[4'-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propan-
oic acid,
3-[3,4'-Difluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-
-ethoxypropanoic acid, and
3-[3'-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic
acid.
37. A method according to claim 1 for the activation of receptors
of PPAR.gamma. and thus for regulating and/or restoring the
metabolism of skin lipids, comprising administering to an
individual in need of such treatment, said effective PPAR.gamma.
receptor-activating amount of said compound having the formula (I),
formulated into a physiologically acceptable medium therefor.
Description
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention
The present invention relates to a novel class of biaromatic
compounds which are activators of receptors of "Peroxisome
Proliferator-Activated Receptor" type of subtype .gamma.
(PPAR.gamma.). This invention also relates to their process of
preparation and to their formulation into pharmaceutical
compositions suited for human or veterinary medicine, or
alternatively for cosmetic compositions.
2. Description of Background and/or Related and/or Prior Art
The activity of receptors of PPAR type has been the subject of many
studies. Mention may be made, by way of indication, of the
publication entitled "Differential Expression of Peroxisome
Proliferator-Activated Receptor Subtypes During the Differentiation
of Human Keratinocytes", Michel Rivier et al., J. Invest.
Dermatol., 1998, 111, 1116-1121, in which a large number of
bibliographic references relating to receptors of PPAR type are
listed. Mention may also be made, by way of indication, of the
report entitled "The PPARs: From Orphan Receptors to Drug
Discovery", Timothy M. Willson et al., J. Med. Chem., 2000, 43,
527-550.
PPAR receptors activate transcription by binding to elements of DNA
sequences, known as peroxisome proliferator response elements
(PPRE), in the form of a heterodimer with retinoid X receptors
(known as RXRs).
Three subtypes of human PPARs have been identified and described:
PPAR.alpha., PPAR.gamma. and PPAR.delta. (or NUC1).
PPAR.alpha. is mainly expressed in the liver, while PPAR.delta. is
ubiquitous.
PPAR.gamma. is the most widely studied of the three subtypes. All
prior art references suggest a critical role for PPAR.gamma. in the
regulation of the differentiation of adipocytes, where it is
greatly expressed. It also plays a key role in systemic lipid
homeostasis.
Furthermore, the assignee hereof has already disclosed, in FR
98/02894, the use of PPAR.gamma.-activating compounds in the
preparation of a pharmaceutical composition, the composition being
intended for the treatment of skin disorders related to an anomaly
in the differentiation of the epidermal cells.
The assignee hereof has also disclosed a class of biaromatic
compounds which are activators of PPAR.gamma. receptors in
FR-2,812,876.
SUMMARY OF THE INVENTION
A novel class of PPAR.gamma.-activating compounds has now been
developed exhibiting biological activities which are significantly
improved with respect to those of the compounds known to the prior
art and in particular with respect to those described in
FR-2,812,876.
According to the present invention, a restricted group of compounds
has now been developed, corresponding to the formula (I) below,
which exhibit a surprising biological activity, in particular a
binding affinity for PPAR.gamma. receptors which is significantly
increased with respect to that of the compounds of FR-2,812,876.
This increased binding affinity emerges in particular from apparent
dissociation constant (KdApp) values which are surprisingly
lowered, as more fully explained below.
Thus, the present invention features novel compounds corresponding
to the following general formula (I):
##STR00002## in which:
R1 is an alkyl radical having 1 to 6 carbon atoms, an acetyl group,
a methylcyclopropane group, an aralkyl radical or an aryl
radical;
R2 is an alkyl radical having 3 to 8 carbon atoms;
R3 is a hydrogen atom or an alkyl radical having 1 to 6 carbon
atoms;
R4 and R5, which may be identical or different, are each a hydrogen
atom, a halogen atom, a hydroxyl radical, an alkyl radical having
from 1 to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or
a trifluoromethyl radical;
and the isomers, optical and/or geometrical, pure or as a mixture,
in all proportions, of the said compounds of formula (I) and the
tautomeric forms, and also the salts of the said compounds of
formula (I).
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 and 2 illustrate a variety of reaction schemes for the
preparation of the compounds according to the present
invention.
DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED
EMBODIMENTS OF THE INVENTION
For the compounds of formula (I) which is presented above, the term
"geometrical isomer" means cis/trans or E/Z isomerism. More
particularly, the possible double bond or bonds present in the
various substituents of the compounds of general formula (I) can be
of E or Z configuration. These geometrical isomers, pure or impure,
alone or as a mixture, are an integral part of the compounds of
formula (I).
The term "optical isomer" embraces all the forms of isomers, alone
or as a mixture, the presence of which results from one or more
axes and/or centres of symmetry in the molecule which results in
the rotation of a beam of polarized light. The term "optical
isomer" comprises more particularly the enantiomers and the
diastereoisomers, in the pure form or as a mixture.
When the compounds according to the invention are provided in the
form of a salt, they are preferably an alkali metal salt, in
particular the sodium salt, or an alkaline earth metal salt or an
organic amine salt, more particularly of amino acids, such as
arginine or lysine.
According to the present invention, the term "alkyl radical having
from 1 to 6 carbon atoms" means, preferably, an optionally
branched, saturated or unsaturated, linear or cyclic alkyl radical
selected from the methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl,
isohexyl, cyclohexyl, ethylenyl, allyl, propenyl, butenyl, pentenyl
or hexenyl radicals.
According to the present invention, the term "alkyl radical having
from 3 to 8 carbon atoms" means, preferably, an optionally
branched, saturated or unsaturated, linear or cyclic alkyl radical
comprising 3 to 8 carbon atoms and preferably the n-propyl,
isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl,
isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl,
isoheptyl, n-octyl, isooctyl, allyl, propenyl, butenyl, pentenyl,
hexenyl, heptenyl or octenyl radicals.
The term "halogen atom" means, preferably, a fluorine, chlorine or
bromine atom.
The term "aralkyl radical" means, preferably, a benzyl, phenethyl
or naphth-2-ylmethyl radical which is unsubstituted or substituted
by one or more radicals selected from among a halogen atom, a
CF.sub.3 radical, an alkyl radical having from 1 to 6 carbon atoms,
an alkoxy radical having from 1 to 6 carbon atoms, a hydroxyl
radical or an amino functional group which is unprotected or
unsubstituted or optionally substituted by at least one alkyl
radical having from 1 to 6 carbon atoms, or a carboxyl functional
group.
The term "aryl radical" means, preferably, a phenyl, biphenyl,
cinnamyl or naphthyl radical which can be mono- or disubstituted by
a halogen atom, a CF.sub.3 radical, an alkyl radical having from 1
to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon
atoms, a nitro functional group, a polyether radical, an aryl
radical, a benzoyl radical, an alkyl ester group, a carboxylic
acid, a hydroxyl radical optionally protected by an acetyl or
benzoyl group, or an amino functional group optionally protected by
an acetyl or benzoyl group or optionally substituted by at least
one alkyl having from 1 to 6 carbon atoms.
The term "alkoxy radical" means, preferably, a methoxy, ethoxy,
isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radical
which can optionally be substituted by an alkyl radical having from
1 to 6 carbon atoms.
The term "polyether radical" means, preferably, a radical having
from 1 to 6 carbon atoms which is interrupted by at least one
oxygen atom, such as the methoxymethoxy, methoxymethylene,
ethoxymethoxy, ethoxymethylene or methoxyethoxymethoxy
radicals.
The term "alkyl ester radical" means a carboxylate functional group
substituted by an alkyl radical having from 1 to 6 carbon
atoms.
Among the compounds of formula (I) above within the scope of the
present invention, the following compounds (alone or as a mixture)
are particularly exemplary: 1.
2(S)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid, 2.
2(S)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid, 3.
2(S)-Cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl--
4-yl]propanoic acid, 4.
2(S)-Propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid, 5.
2(S)-Benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]prop-
anoic acid, 6.
2(S)-Allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid, 7.
2(S)-Cyclopropylmethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl--
4-yl]propanoic acid, 8.
3-[3'-(1-Methyl-3-pentylureido)biphenyl-4-yl]-2(S)-propoxypropanoic
acid, 9.
2(S)-Allyloxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid, 10.
2(S)-Benzyloxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]pro-
panoic acid, 11.
2(S)-Methoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid, 12.
3-[3'-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropanoic
acid, 13.
2(S)-Ethoxy-3-[3'-(1-methyl-3-propylureido)biphenyl-4-yl]propan-
oic acid, 14.
3-[3'-(3-Cyclopropylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropa-
noic acid, 15.
3-[3'-(3-Cyclopentylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropa-
noic acid, 16.
2(S)-Ethoxy-3-[3-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propano-
ic acid, 17.
2(S)-Ethoxy-3-[4'-fluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propan-
oic acid, 18.
3-[3,4'-Difluoro-3'-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-ethoxypr-
opanoic acid, 19. Methyl
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate,
20. Methyl
2(S)-cyclopropylmethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4--
yl]propanoate, 21.
2(S)-Cyclopropylmethoxy-3-[3'-(3-cyclopropylmethyl-1-methylureido)bipheny-
l-4-yl]propanoic acid, 22.
3-{3'-[3-(2-Cyclohexylethyl)-1-methylureido]biphenyl-4-yl}-2(S)-ethoxypro-
panoic acid, 23.
2(R)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid, 24.
2(R)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid, 25.
2-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid, 26.
2(R)-Allyloxy-3[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propa-
noic acid, 27.
3-[3'-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic
acid, 28. Allyl
3-[3'-(3-allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropano-
ate.
According to the present invention, the compounds of formula (I)
which are more particularly preferred are those which exhibit at
least one of the following characteristics:
R1 is an alkyl radical selected from among the methyl, ethyl,
n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl
radicals, a methylcyclopropane group or a benzyl radical,
R2 is an alkyl radical selected from among the n-pentyl, isopentyl,
cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptyl
radicals,
R3 is a hydrogen atom,
R4 and/or R5 are a hydrogen atom or a fluorine atom.
In particular, according to the present invention, preferred are
the compounds of formula (I) exhibiting all of the following
characteristics:
R1 is an alkyl radical selected from among the methyl, ethyl,
n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl
radicals, a methylcyclopropane group or a benzyl radical,
R2 is an alkyl radical selected from among the n-pentyl, isopentyl,
cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptyl
radicals,
R3 is a hydrogen atom,
R4 and/or R5 are a hydrogen atom or a fluorine atom.
More particularly, the present invention features a process for the
synthesis of the compounds corresponding to the general formula (I)
or of the possible isomers, optical and/or geometrical, pure or as
a mixture, in all proportions, of the said compounds of formula
(I), of the possible tautomeric forms, or of the salts of the said
compounds of formula (I), comprising the following stages:
in the stages described below, which relate to FIG. 1, unless
otherwise indicated, the R1, R2, R3, R4 and R5 radicals of the
compounds 1 to 20 are the same as those defined for the compounds
of general formula (I).
a) Preparation of the Compound of Formula 1:
##STR00003## from commercial 3-bromoaniline optionally substituted
by an R5 group, by protecting the amine with di(tert-butyl)
dicarbonate and by then carrying out a methylation, for example
with methyl iodide, in the presence of sodium hydride;
b) Preparation of Compound 2:
##STR00004## by treating compound 1 with an acid, such as, for
example, trifluoroacetic acid;
c) Preparation of Compound 3:
##STR00005## by the reaction of compound 2 with pinacolborane in
the presence of a catalyst, such as palladium dichloride
diphenylphosphinopropane ferrocene;
d) Preparation of Compound 5:
##STR00006## by treating the commercial epoxide 4:
##STR00007## with an aryl cuprate obtained by reaction of an aryl
halide, such as, for example, 1,4-dibromobenzene, in the presence
of tert-butyllithium and of copper cyanide;
e) Preparation of Compound 6:
##STR00008## by reacting compound 5 with an alkyl halide, such as
ethyl iodide, for example, in the presence of silver oxide, to
prevent any problem of racemization;
f) Preparation of Compound 7:
##STR00009## by the coupling of compound 6 and compound 3 according
to a reaction of Suzuki type in the presence of
tetrakis(triphenylphosphine)palladium;
g) Preparation of Compound 8:
##STR00010## by the reaction from compound 7 and an alkyl
isocyanate, such as, for example, heptyl isocyanate;
h) Preparation of Compound (I):
##STR00011##
h1) when R3 is an alkyl radical: by transesterification of compound
8 with an alcohol in the presence of an acid, such as sulfuric
acid, or
h2) when R3 is a hydrogen atom: by saponification of compound 8 in
the presence of a base, such as, for example, sodium hydroxide.
According to another advantageous process for the synthesis of the
compounds of formula (I), the stages for preparing compound 3 are
repeated as defined in parts a) to c) and the stages for preparing
compound 5 are repeated as defined in part d) and are followed by
the stages set out below:
i) Preparation of Compound 10:
##STR00012## by treating compound 5 with a benzyl halide, such as,
for example, benzyl bromide, in the presence of silver oxide;
j) Preparation of compound 11:
##STR00013## by coupling compound 10 with compound 3 by a reaction
of Suzuki type using a palladium catalyst, such as, for example,
tetrakis(triphenylphosphine)palladium;
k) Preparation of Compound 12:
##STR00014## by the reaction from compound 11 and an alkyl
isocyanate, such as, for example, heptyl isocyanate;
l) Preparation of the Alcohol 13:
##STR00015## by hydrogenolysis of compound 12 with hydrogen in the
presence of palladium-on-charcoal;
m) Preparation of Compound 8:
##STR00016## by reacting compound 13 with an alkyl halide, such as
allyl bromide, for example, in the presence of silver oxide;
n) Preparation of Compound (I) from Compound 8 as Defined in Stage
h), the Alternatives n1) and n2) being Identical to the
Alternatives h1) and h2).
The compounds of formula (I) can also be obtained according to the
reaction scheme presented by the synthetic route 2a of FIG. 2 from
aldehyde derivatives 15 according to a reaction of Horner type with
a phosphonate 16 in the presence of a base, such as sodium hydride,
butyllithium or potassium tert-butoxide, then hydrogenation in the
presence of palladium-on-charcoal and optionally enzymatic
resolution, for example in the presence of the enzyme proteinase
2A, to obtain the (S) enantiomer. According to this method of
synthesis, R1, R2, R3, R4 and R5 are as defined above.
The compounds of formula (I) can also be obtained according to the
reaction scheme presented by the synthetic route 2b of FIG. 2 by
the reaction of 4(S)-benzyloxazolidin-2-one and of a 2-alkoxyacetic
acid chloride for the preparation of an Evans derivative, followed
by the condensation of such an Evans derivative, of well-defined
chirality, with the aldehyde derivative 15 in the presence of
dibutylboron triflate, for example, which results in the derivative
19. The deoxygenation of compound 19 by the Barton reaction results
in compound 20. Compound (I) is obtained from compound 20 by
saponification, for example in the presence of lithium hydroxide,
or by transesterification, for example with sodium methoxide in
methanol. According to this method of synthesis, R1, R2, R3, R4 and
R5 are as defined above.
According to the present invention, the term "Evans derivative"
means, preferably, an oxazolidin-2-one derivative of well-defined
chirality, such as a 4(S)-benzyloxazolidin-2-one derivative.
According to the present invention, the term "Barton reaction"
means the reaction of phenyl chlorothionoformate with the hydroxyl
group of compound 19, in the case of the synthetic route 2b
considered in FIG. 2, followed by a radical reaction in the
presence of tributyltin hydride.
The compounds according to the invention exhibit modulatory
properties with regard to receptors of PPAR type. This activity on
PPAR.alpha., .delta. and .gamma. receptors is measured in a
transactivation test and quantified by the apparent dissociation
constant (KdApp), as described in Example 7 below.
In a manner not obvious to one skilled in the art in the light of
the prior art, the preferred compounds according to the invention
exhibit a surprising biological activity, in particular a binding
affinity for PPAR.delta. receptors which is significantly increased
with respect to that of the compounds according to FR-2,812,876.
The KdApp values of the compounds according to the present
invention for PPAR.gamma. receptors are listed in Example 7 and are
illustrated in Table 1, where they are compared with those of the
compounds of FR-2,812,876: it is apparent that they are less than 1
nM and advantageously less than 0.1 nM, i.e., at least 120 times
lower and up to several thousand times lower than the KdApp values
described for the compounds of FR-2,812,876 (Table 1), reflecting a
considerably increased affinity of the compounds according to the
present invention for PPAR.gamma. receptors. In Table 1, the KdApp
values, with PPAR.gamma. receptors, of certain compounds according
to the invention are compared with certain compounds according to
the prior art, the compounds exhibiting similar substituents being
considered. In particular, the R1 radical according to the
invention is equivalent to the R10 radical of the compounds
according to FR-2,812,876 and the R2 radical according to the
invention is equivalent to the R4 radical of the compounds
according to FR-2,812,876.
In particular, the compounds according to the invention are
modulators of specific receptors of PPAR.gamma. type, that is to
say that they exhibit a ratio of the KdApp for the PPAR.alpha. or
PPAR.delta. receptors to the KdApp for the PPAR.gamma. receptors of
greater than or equal to 10. Preferably, this
PPAR.alpha./PPAR.gamma. or PPAR.delta./PPAR.gamma. ratio is greater
than or equal to 50 and more advantageously greater than or equal
to 100.
The present invention also features the compounds of formula (I) as
described above as medicaments.
The compounds according to the invention are particularly well
suited for the following treatments:
1) of dermatological conditions linked to a disorder of
keratinization involving differentiation and proliferation, in
particular for treating acne vulgaris, comedonic or polymorphic
acne, acne rosacea, nodulocystic acne, acne conglobata, senile acne
and secondary acnes, such as solar, drug or occupational acne,
2) of other types of disorders of keratinization, in particular
ichthyoses, ichthyosiform conditions, Darrier's disease,
palmoplantar keratoderma, leucoplakia and leucoplakiform conditions
or cutaneous or mucosal (oral) lichen,
3) of other dermatological conditions or afflictions having an
inflammatory immunoallergic component, with or without cell
proliferation disorder, and, in particular, all forms of psoriasis,
whether cutaneous, mucosal or ungual, and even psoriatic
rheumatism, or alternatively cutaneous atopy, such as eczema, or
respiratory atopy or alternatively gingival hypertrophy,
4) of all dermal or epidermal proliferations, whether they are
benign or malignant and whether they are or are not of viral
origin, such as common warts, flat warts and epidermodysplasia
verruciformis, florid or oral papillomatoses, T lymphoma, and the
proliferations which can be induced by ultraviolet radiation, in
particular in the case of basal cell and prickle cell epithelioma,
and also all precancerous skin lesions, such as
keratoacanthomas,
5) of other dermatological disorders, such as immune dermatoses,
such as lupus erythematosus, immune bullous diseases and collagen
diseases, such as scleroderma,
6) of dermatological or general conditions or afflictions having an
immunological component,
7) of skin disorders due to exposure to UV radiation, and also for
repairing or combating skin aging, whether photoinduced or
chronologic or for reducing actinic keratoses and pigmentations or
any pathology associated with chronologic or actinic aging, such as
xerosis,
8) of disorders of the sebaceous function, such as hyperseborrhoea
of acne or simple seborrhoea,
9) or the prevention of disorders of cicatrization or the
prevention or the repair of stretch marks,
10) of disorders of pigmentation, such as hyperpigmentation,
melasma, hypopigmentation or vitiligo,
11) of conditions of the metabolism of lipids, such as obesity,
hyperlipidaemia or non-insulin-dependent diabetes,
12) of inflammatory conditions, such as arthritis,
13) or the prevention of cancerous or precancerous conditions,
14) or the prevention of alopecia of various origins, in particular
alopecia due to chemotherapy or to radiation,
15) of disorders of the immune system, such as asthma, type I
diabetes mellitus, multiple sclerosis or other selective
dysfunctions of the immune system,
16) of conditions of the cardiovascular system, such as
arteriosclerosis or hypertension.
The present invention also features pharmaceutical or cosmetic
compositions comprising, formulated into a physiologically
acceptable medium, at least one compound of formula (I) as defined
above.
This invention also features the use of the compounds of formula
(I) in the manufacture of compositions suited for the treatment of
the abovementioned conditions, in particular for regulating and/or
restoring the metabolism of skin lipids.
The compositions according to the invention can be administered
orally, parenterally, topically or ocularly. Preferably, the
pharmaceutical composition is packaged in a form suitable for
topical application.
Orally, the composition, more particularly the pharmaceutical
composition, can be provided in the form of tablets, including
sugar-coated tablets, hard gelatin capsules, syrups, suspensions,
solutions, powders, granules, emulsions or lipid or polymeric
microspheres or nanospheres or vesicles which make possible
controlled release. Parenterally, the composition can be provided
in the form of solutions or suspensions for infusion or for
injection.
The compounds according to the invention are generally administered
at a daily dose of approximately 0.001 mg/kg to 100 mg/kg of body
weight, taken 1 to 3 times.
The compounds are administered systemically at a concentration
generally of from 0.001% to 10% by weight, preferably from 0.01% to
1% by weight, with respect to the weight of the composition.
Topically, the pharmaceutical composition according to the
invention is more particularly suited for the treatment of the skin
and mucous membranes and can be provided in the form of salves,
creams, milks, ointments, powders, impregnated pads, solutions,
gels, sprays, lotions or suspensions. It can also be provided in
the form of lipid or polymeric microspheres or nanospheres or
vesicles or of polymeric patches and of hydrogels which make
possible controlled release. This topical composition can be
provided in the anhydrous form, in the aqueous form or in the form
of an emulsion.
The compounds are administered topically at a concentration
generally of from 0.001% to 10% by weight, preferably from 0.01% to
1% by weight, with respect to the total weight of the
composition.
The compounds of formula (I) according to the invention also have
an application in the cosmetics field, in particular in body and
hair hygiene and more particularly for regulating and/or restoring
the metabolism of skin lipids. In comparison with the products
known previously, these compounds of formula (I) have the advantage
of additionally exhibiting other advantageous properties, in
particular anti-inflammatory or soothing properties, which makes
them less irritating and therefore better tolerated compounds.
The present invention also features the cosmetic use of a
composition comprising, formulated into a physiologically
acceptable vehicle, at least one of the compounds of formula (I)
for body or hair hygiene.
The cosmetic compositions according to the invention, comprising,
in a cosmetically acceptable vehicle, at least one compound of
formula (I) or one of its optical or geometrical isomers or one of
its salts, can be provided in particular in the form of a cream, a
milk, a lotion, a gel, lipid or polymeric microspheres or
nanospheres or vesicles, a soap or a shampoo.
The concentration of compound of formula (I) in the subject
cosmetic compositions ranges from 0.001% to 3% by weight, with
respect to the total weight of the composition.
The compositions as described above can, of course, additionally
comprise inert or even pharmacodynamically active additives or
combinations of these additives and in particular: wetting agents;
depigmenting agents, such as hydroquinone, azelaic acid, caffeic
acid or kojic acid; emollients; moisturizing agents, such as
glycerol, polyethylene glycol (PEG) 400, thiamorpholinone and its
derivatives, or urea; anti-seborrhoeic or anti-acne agents, such as
S-carboxymethylcysteine, S-benzylcysteamine, their salts or their
derivatives, or benzoyl peroxide; anti-fungal agents, such as
ketoconazole or 4,5-polymethylene-3-isothiazolidones;
anti-bacterials; carotenoids and in particular .beta.-carotene;
anti-psoriatic agents, such as anthralin and its derivatives;
eicosa-5,8,11,14-tetraynoic and eicosa-5,8,11-triynoic acids, their
esters and amides; and, finally, retinoids. The compounds of
formula (I) can also be combined with vitamins D or their
derivatives, with corticosteroids, with agents for combating free
radicals, with .alpha.-hydroxy or a-keto acids or their
derivatives, or with ion-channel blockers.
These compositions can also comprise flavor enhancers,
preservatives, such as esters of para-hydroxybenzoic acid,
stabilizing agents, moisture-regulating agents, pH-regulating
agents, agents for modifying osmotic pressure, emulsifying agents,
UV-A and UV-B screening agents, or antioxidants, such as
.alpha.-tocopherol, butylated hydroxyanisole or butylated
hydroxytoluene.
Of course, one skilled in this art will take care to select the
optional compound or compounds to be added to these compositions so
that the advantageous properties intrinsically associated with the
present invention are not, or not substantially, detrimentally
affected by the envisaged addition.
The present invention also features a cosmetic regime or regimen
for rendering the skin more attractive, wherein a composition
comprising at least one compound of formula (I) as defined above is
topically applied onto the skin. The regulation and/or the
restoration of the metabolism of skin lipids makes it possible to
obtain skin with a surface appearance which has been rendered more
attractive.
In order to further illustrate the present invention and the
advantages thereof, the following specific examples of active
compounds are given, as are the results of the biological
activities thereof, it being understood that same are intended only
as illustrative and in nowise limitative. In said examples to
follow, all parts and percentages are given by weight, unless
otherwise indicated.
EXAMPLE 1
Synthesis of
2(S)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid
a) Preparation of tert-Butyl (3-bromophenyl)carbamate
120 g (549 mmol) of di(tert-butyl) dicarbonate are added in small
amounts at ambient temperature to a mixture of 94 g (549 mmol) of
3-bromoaniline and 1 l of dichloromethane. After stirring for 18
hours, the reaction mixture is poured into ice-cold water and
extracted with dichloromethane. The organic phase is separated by
settling, dried over magnesium sulfate and evaporated. 138 g of
tert-butyl (3-bromobenzyl)carbamate are obtained. Yield=98%.
b) Preparation of tert-Butyl (3-bromophenyl)-N-methylcarbamate
19 g (475 mmol) of sodium hydride (60% in oil) are added in small
amounts to a solution of 114 g (447 mmol) of tert-butyl
(3-bromobenzyl)carbamate in 800 ml of dimethylformamide and the
reaction medium is stirred until evolution of gas has ceased. 29.3
ml (470 mmol) of methyl iodide are added dropwise and stirring is
maintained for 18 hours. The reaction medium is poured into
ice-cold water and extracted with ethyl acetate. The organic phase
is separated by settling, dried over magnesium sulfate and
evaporated. 115 g of tert-butyl (3-bromobenzyl)-N-methylcarbamate
are obtained. Yield=95%.
c) Preparation of tert-Butyl
(4'-formylbiphenyl-3-yl)methylcarbamate
307 ml (615 mmol) of an aqueous potassium carbonate solution (2M)
are added dropwise to a mixture of 61.5 g (205 mmol) of tert-butyl
(3-bromobenzyl)-N-methylcarbamate, 46 g (307 mmol) of
4-formylbenzeneboronic acid and 500 ml of toluene. The reaction
medium is subsequently degassed with argon and 7 g (6.2 mmol) of
tetrakis(triphenylphosphine)palladium(0) are added. After heating
at 90.degree. C. for 24 hours, the reaction medium is poured into
water and extracted with ethyl acetate. The organic phase is
separated by settling, dried over magnesium sulfate and evaporated.
The residue obtained is purified by chromatography on a silica
column eluted with a mixture of heptane and ethyl acetate (70/30).
After evaporating the solvents, 67 g of tert-butyl
(4'-formylbiphenyl-3-yl)methylcarbamate are collected.
Yield=60%.
d) Preparation of tert-Butyl
{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxop-
ropyl]biphenyl-3-yl}methylcarbamate
72.3 ml (72.3 mmol) of dibutylboron triflate and then 12.6 ml (72.3
mmol) of diisopropylethylamine are added dropwise to a solution,
cooled to 0.degree. C., of 15.2 g (57.8 mmol) of
(S)-4-benzyl-3-(2-ethoxyacetyl)oxazolidin-2-one, prepared as
described in the publication by Bernard Hulin et al., J. Med.
Chem., 1996, 39, 3897-3907, from commercial
(S)-4-benzyloxazolidin-2-one, in 150 ml of dichloromethane. The
reaction medium is stirred at 0.degree. C. for 30 min and then
cooled to -78.degree. C. A solution of 15 g (48.2 mmol) of
tert-butyl (4'-formylbiphenyl-3-yl)methylcarbamate in 70 ml of
dichloromethane is then added dropwise. After stirring from
-78.degree. C. to ambient temperature over 4 hours, the reaction
medium is cooled to 0.degree. C. and a mixture of 130 ml of a
buffer solution, pH=7, and of 100 ml of methanol is added dropwise,
followed by the dropwise addition of a mixture of 130 ml of aqueous
hydrogen peroxide solution and of 100 ml of methanol. The reaction
medium is stirred at 0.degree. C. for 1 hour and then at ambient
temperature for 3 hours. After addition of water, the reaction
medium is extracted with dichloromethane. The organic phase is
dried over magnesium sulfate, filtered and evaporated under vacuum.
The residue obtained is purified by chromatography on a silica
column eluted with a mixture of heptane and ethyl acetate (70/30)
and then increase in the polarity up to a 50/50 heptane/ethyl
acetate mixture. After evaporation of the solvents, 28 g of
tert-butyl
{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxop-
ropyl]biphenyl-3-yl}methylcarbamate are collected. Yield=81%.
e) Preparation of tert-Butyl
(S)-{4'-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl--
3-yl}methylcarbamate
4.8 ml (9.6 mmol) of sodium bis(trimethylsilylamide) are added
dropwise to a solution, cooled beforehand to 0.degree. C., of 5 g
(8.7 mmol) of tert-butyl
{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxop-
ropyl]biphenyl-3-yl}methylcarbamate in 70 ml of tetrahydrofuran.
The reaction medium is stirred at -78.degree. C. for 1 hour, then
1.3 ml (9.6 mmol) of phenyl chlorothionoformate are added and the
medium is stirred at -78.degree. C. for 1 hour and then at ambient
temperature for 1 hour 30 min. After evaporation of the
tetrahydrofuran, the reaction medium is extracted with
dichloromethane and washed with water. The organic phase is
separated by settling, dried over magnesium sulfate, filtered and
evaporated under vacuum. The 9 g (8.7 mmol) of residue obtained are
placed in 100 ml of toluene and 71 mg (0.4 mmol) of
2,2'-azobis(2-methylpropionitrile) and then 3.5 ml (13.1 mmol) of
tributyltin hydride are added. The reaction medium is heated at
110.degree. C. for 20 minutes. After addition of water, the
reaction medium is extracted with ethyl acetate. The organic phase
is washed with water and with a saturated aqueous sodium chloride
solution, dried over magnesium sulfate, filtered and evaporated.
The residue obtained is purified by chromatography on a silica
column eluted with a mixture of heptane and ethyl acetate (90/10)
and then increase in the polarity up to a 70/30 heptane/ethyl
acetate mixture. After evaporation of the solvents, 2.85 g of
tert-butyl
(S)-{4'-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl--
3-yl}methylcarbamate are obtained. Yield=60%.
f) Preparation of
4(S)-Benzyl-3-[2(S)-ethoxy-3-(3'-(methylamino)biphenyl-4-yl)propionyl]oxa-
zolidin-2-one
9 ml (114 mmol) of trifluoroacetic acid are added dropwise to a
solution of 8.5 g (15.2 mmol) of
(S)-{4'-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl--
3-yl}methylcarbamate in 150 ml of dichloromethane. The reaction
medium is stirred at ambient temperature for 24 h, added to water
and extracted with dichloromethane. The organic phase is dried over
magnesium sulfate, filtered and evaporated. 8.7 g of
4(S)-benzyl-3-[2(S)-ethoxy-3-(3'-(methylamino)biphenyl-4-yl)propionyl]oxa-
zolidin-2-one are obtained in the form of a trifluoroacetate salt.
Yield=100%.
g) Preparation of
1-{4'-[3-(4(S)-Benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphe-
nyl-3-yl}-3-heptyl-1-methylurea
1.1 ml (7.7 mmol) of triethylamine and then 2.25 ml (14.0 mmol) of
heptyl isocyanate are added dropwise to a solution of 4 g (7.0
mmol) of
4(S)-benzyl-3-[2(S)-ethoxy-3-(3'-(methylamino)biphenyl-4-yl)propionyl]oxa-
zolidin-2-one in 50 ml of dichloromethane. After stirring at
ambient temperature for 20 hours, the reaction medium is placed in
water and extracted with dichloromethane. The organic phase is
dried over magnesium sulfate, filtered and evaporated. The residue
obtained is purified by chromatography on a silica column eluted
with a mixture of heptane and ethyl acetate (50/50). After
evaporation of the solvents, 3.6 g of
1-{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphe-
nyl-3-yl}-3-heptyl-1-methylurea are collected in the form of a
colorless oil. Yield=86%.
h) Synthesis of
2(S)-Ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid
18 ml (9.0 mmol) of a 0.5M aqueous lithium hydroxide solution are
added to a solution, cooled beforehand to 0.degree. C., of 3.6 g
(6.0 mmol) of
1-{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphe-
nyl-3-yl}-3-heptyl-1-methylurea in 80 ml of tetrahydrofuran. The
reaction medium is stirred at 0.degree. C. for 2 hours, then a
portion of the tetrahydrofuran is evaporated, and water and
n-butanol are added. The reaction medium is acidified with a 1N
hydrochloric acid solution to pH 3 and extracted with n-butanol.
The organic phase is dried over magnesium sulfate, filtered and
evaporated under vacuum. The residue obtained is purified by
chromatography on a silica column eluted with a mixture of heptane
and ethyl acetate (70/30) and then increase in the polarity up to a
50/50 heptane/ethyl acetate mixture. After evaporation of the
solvents, 1.5 g of
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propano-
ic acid are collected in the form of a colorless oil.
Yield=57%.
.sup.1H NMR (.delta., CDCl.sub.3): 0.87 (t, J=7 Hz, 3H); 1.20-1.24
(m, 8H), 1.43 (m, 2H), 3.12 (m, 1H), 3.18 (m, 1H), 3.22 (m, 2H),
3.32 (s, 3H), 3.49 (m, 1H), 3.69 (m, 1H), 4.15 (m, 1H), 4.43 (m,
1H), 7.22-7.56 (m, 8H).
i) Preparation of L-Arginine salt of
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid
An aqueous solution of 0.4 g (2.3 mmol) of L-arginine is added
dropwise to a solution, heated beforehand to 78.degree. C., of 1 g
(2.3 mmol) of
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid in 22 ml of ethanol. The reaction medium is heated at
78.degree. C. for 1 hour, then it is brought back to ambient
temperature overnight and evaporated to dryness under vacuum. The
residue obtained is taken up in 15 ml of ethyl ether, stirred at
ambient temperature for 30 min and filtered off. The solid obtained
is rinsed with ethyl ether and dried under vacuum in an oven. 1.3 g
of the L-arginine salt of
2(S)-ethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid are obtained in the form of a white powder. Yield=100%.
.sup.1H NMR (.delta., d.sub.6-DMSO): 0.84 (m, 3H), 1.00 (m, 3H),
1.22 (m, 8H), 1.37 (m, 2H), 1.27-1.39 (m, 4H), 2.90 (m, 1H),
2.97-3.07 (m, 3H), 3.18 (s, 3H), 3.20 (m, 1H), 3.60 (m, 1H), 3.67
(m, 1H), 6.05 (m, 1H), 7.18-7.54 (m, 8H).
EXAMPLE 2
Synthesis of
2(S)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid
a) Preparation of
1-{4'-[3-(4(S)-Benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphe-
nyl-3-yl}-1-methyl-3-pentylurea
In a manner analogous to Example 1g), from 0.8 g (1.4 mmol) of
4(S)-benzyl-3-[2(S)-ethoxy-3-(3'-(methylamino)biphenyl-4-yl)propionyl]oxa-
zolidin-2-one and 0.35 ml (2.8 mmol) of pentyl isocyanate, 0.54 g
of
1-{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphe-
nyl-3-yl}-1-methyl-3-pentylurea is obtained in the form of a
colorless oil. Yield=67%.
b) Synthesis of
2(S)-Ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid
In a manner analogous to Example 1h), from 0.53 g (0.93 mmol) of
1-{4'-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphe-
nyl-3-yl}-1-methyl-3-pentylurea and 2.8 ml (1.4 mmol) of a 0.5N
aqueous sodium hydroxide solution, 0.32 g of
2(S)-ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid is obtained in the form of a colorless oil. Yield=84%.
.sup.1H NMR (.delta., CDCl.sub.3): 0.87 (t, J=7 Hz, 3H), 1.21 (t,
J=7 Hz, 3H), 1.25-1.37 (m, 8H), 1.60 (m, 2H), 3.11 (dd, J=7.8 Hz,
J=14 Hz, 1H), 3.38 (dd, J=7 Hz, J=14 Hz, 1H), 3.40 (m, 2H), 3.47
(m, 3H), 3.50 (m, 1H), 3.65 (m, 1H), 4.15 (m, 1H), 6.94 (d, J=8.4
Hz, 1H), 7.35-7.40 (m, 3H), 7.75-7.82 (m, 3H).
c) Preparation of L-Arginine salt of
2(S)-ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid
In a manner analogous to Example 1i), from 0.32 g (0.8 mmol) of
2(S)-ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid and 0.13 g (0.8 mmol) of arginine, 0.45 g of the L-arginine
salt of
2(S)-ethoxy-3-[3'-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic
acid is obtained in the form of a white solid. Yield=100%.
.sup.1H NMR (.delta., d.sub.6-DMSO): 0.86 (t, J=7 Hz, 3H), 1.01 (t,
J=7 Hz, 3H), 1.20-1.28 (m, 8H), 1.30 (m, 2H), 1.40 (m, 2H),
1.41-1.57 (m, 2H), 2.8 (m, 1H), 3.00-3.10 (m, 4H), 3.20 (s, 3H),
3.22 (m, 1H), 3.33 (m, 1H), 3.42 (m, 1H), 3.67 (m, 1H), 6.06 (m,
1H), 7.19-7.55 (m, 8H).
EXAMPLE 3
Synthesis of
2(S)-Cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]prop-
anoic acid
a) 3.6 g (12.7 mmol) of tert-butyl
(3-bromophenyl)-N-methylcarbamate, prepared in a manner analogous
to Example 1b), are dissolved in 15 ml of dichloromethane. 5 ml of
trifluoroacetic acid are added and the reaction mixture is stirred
at ambient temperature for 1 hour. The reaction is halted by the
addition of 50 ml of a saturated sodium hydrogencarbonate solution
and then extraction is carried out with ethyl acetate. The organic
phases are combined and dried over sodium sulfate. The solvents are
evaporated and then the residue is chromatographed on silica gel
(heptane/ethyl acetate 50/50). 2.14 g of 3-bromo-N-methylaniline
are obtained in the form of an oil. Yield=90%.
b) 890 mg (3.5 mmol) of pinacolborane are added to a mixture of 600
mg (3.2 mmol) of 3-bromo-N-methylaniline and 1 g (10.2 mmol) of
potassium acetate in the presence of 130 mg (0.16 mmol, 5 mol %) of
palladium dichloride diphenylphosphinopropane ferrocene
(PdCl.sub.2dppf) in 10 ml of dimethylformamide. The mixture is
stirred at 90.degree. C. for 2 hours. The reaction is halted by the
addition of 20 ml of water and then extraction is carried out with
ethyl acetate. The organic phases are combined and dried over
sodium sulfate. The solvents are evaporated and then the residue is
chromatographed on silica gel (heptane/ethyl acetate 80/20). 420 mg
of
methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine
are obtained in the form of an oil. Yield=57%.
c) 72 ml (0.122 mol, 2.5 eq) of tert-butyllithium (1.7M/pentane)
are added slowly using a needle to a suspension of 35 g (0.148 mol,
3 eq) of 1,4-dibromobenzene in 100 ml of tert-butyl methyl ether at
-30.degree. C. The mixture is stirred at -30.degree. C. for 10 min
and then 5.3 g (0.059 mol) of copper(I) cyanide are introduced into
the above solution. The reaction mixture is stirred at -30.degree.
C. for 20 min. A solution of 5 g (0.049 mol) of methyl
(S)-glycidate in 10 ml of tert-butyl methyl ether is added while
keeping the temperature below -20.degree. C. The mixture is stirred
at -30.degree. C. for 20 min and then the reaction is halted by the
addition of a saturated ammonium chloride solution. The mixture is
extracted with 3.times.300 ml of ethyl acetate. The organic phases
are combined and dried over sodium sulfate. The solvents are
evaporated and then the residue is chromatographed on silica gel
(heptane 100% up to heptane/ethyl acetate 60/40). 7.2 g of methyl
(S)-3-(4-bromophenyl)-2-hydroxypropionate are obtained in the form
of a solid. Yield=56%.
d) 0.11 ml (1.15 mmol) of bromomethylcyclopropane are added to a
mixture of 267 mg (3.48 mmol) of silver oxide and 100 mg (0.38
mmol) of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate in 2 ml
of diethyl ether. The reaction mixture is stirred at 50.degree. C.
for 24 hours. The mixture is filtered and then the solvents are
evaporated. The residue is chromatographed on silica gel
(heptane/ethyl acetate 85/15). 145 mg of methyl
(S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propanoate are obtained
in the form of an oil. Yield=50%.
e) 53 mg (0.046 mmol) of tetrakis(triphenylphosphine)palladium are
added to a solution of 145 mg (0.46 mmol) of methyl
(S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propionate and 129 mg
(0.55 mmol) of
methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ami-
ne in 3 ml of dimethylformamide. 0.3 ml of a 2M potassium phosphate
solution is added and the reaction mixture is stirred at 90.degree.
C. for 2 hours. The reaction is halted by the addition of 10 ml of
water and then extraction is carried out with ethyl acetate. The
organic phases are combined and dried over sodium sulfate. The
solvents are evaporated and then the residue is chromatographed on
silica gel (heptane/ethyl acetate 80/20). 70 mg of methyl
(S)-2-cyclopropylmethoxy-3-[3'-(methylamino)biphenyl-4-yl]propanoate
are obtained in the form of an oil. Yield=45%.
f) 40 .mu.l (0.25 mmol) of heptyl isocyanate are added to a
solution of 70 g (0.2 mmol) of methyl
(S)-2-cyclopropylmethoxy-3-[3'-(methylamino)biphenyl-4-yl]propionate
in 2 ml of dichloromethane. The reaction mixture is stirred at
ambient temperature for 48 hours. The reaction is halted by the
addition of 2 ml of water and then extraction is carried out with
ethyl acetate. The organic phases are combined and dried over
sodium sulfate. The solvents are evaporated and then the residue is
chromatographed on silica gel (heptane/ethyl acetate 70/30). 86 mg
of methyl
(S)-2-cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]pro-
panoate are obtained in the form of an oil. Yield=87%.
g) 21 mg (0.54 mmol) of sodium hydroxide are added to a solution of
86 mg (0.18 mmol) of methyl
(S)-2-cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]pro-
pionate in 2 ml of 9/1 tetrahydrofuran/methanol. The reaction
mixture is stirred at ambient temperature overnight. The reaction
is halted by the addition of 2 ml of water and 0.5 ml of acetic
acid, and then extraction is carried out with ethyl acetate. The
organic phases are combined and dried over sodium sulfate. The
solvents are evaporated and then the residue is chromatographed on
silica gel (dichloromethane/methanol 90/10). 70 mg of
2(S)-cyclopropylmethoxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]prop-
anoic acid are obtained in the form of an oil. Yield=84%.
.sup.1H NMR: (CDCl.sub.3, 400 MHz): 0.20 (m, 2H), 0.56 (m, 2H),
0.86 (t, J=6.8 Hz, 3H), 1.05 (m, 1H), 1.24 (m, 8H), 1.42 (m, 2H),
3.07-3.25 (m, 4H), 3.32 (s, 3H), 3.39 (m, 2H), 4.20 (dd, J=4, 7.6
Hz, 1H), 4.40 (t, J=5.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.38 (d,
J=8.4 Hz, 2H), 7.47-7.54 (m, 5H).
EXAMPLE 4
Synthesis of
2-(S)-Propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid
a) 0.22 ml (2.31 mmol) of propyl iodide is added to a mixture of
793 mg (3.48 mmol) of silver oxide and 300 mg (1.16 mmol) of methyl
(S)-3-(4-bromophenyl)-2-hydroxypropionate in 3 ml of diethyl ether.
The reaction mixture is stirred at 50.degree. C. for 12 hours. The
mixture is filtered and then the solvents are evaporated. The
residue is chromatographed on silica gel (heptane/ethyl acetate
80/20). 291 mg of methyl
(S)-3-(4-bromophenyl)-2-(propyloxy)propanoate are obtained in the
form of an oil. Yield=83%.
b) 38 mg (0.033 mmol) of tetrakis(triphenylphosphine)palladium are
added to a solution of 100 mg (0.33 mmol) of methyl
(S)-3-(4-bromophenyl)-2-(propyloxy)propionate and 90 mg (0.39 mmol)
of
methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine
in 1 ml of dimethylformamide. 0.2 ml of a 2M potassium phosphate
solution is added and the reaction mixture is stirred at 90.degree.
C. for 2 hours. The reaction is halted by the addition of 10 ml of
water and then extraction is carried out with ethyl acetate. The
organic phases are combined and dried over sodium sulfate. The
solvents are evaporated and then the residue is chromatographed on
silica gel (heptane/ethyl acetate 80/20). 76 mg of methyl
(S)-2-propyloxy-3-[3'-(methylamino)biphenyl-4-yl]propanoate are
obtained in the form of an oil. Yield=70%.
c) 156 .mu.l (0.96 mmol) of heptyl isocyanate are added to a
solution of 210 mg (0.64 mmol) of methyl
(S)-2-propyloxy-3-[3'-(methylamino)biphenyl-4-yl]propanoate in 3 ml
of dichloromethane. The reaction mixture is stirred at ambient
temperature for 48 hours. The reaction is halted by the addition of
2 ml of water and then extraction is carried out with ethyl
acetate. The organic phases are combined and dried over sodium
sulfate. The solvents are evaporated and then the residue is
chromatographed on silica gel (heptane/ethyl acetate 70/30). 200 mg
of methyl
(S)-2-propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
are obtained in the form of an oil. Yield=66%.
d) 51 mg (1.28 mmol) of sodium hydroxide are added to a solution of
200 mg (0.42 mmol) of methyl
(S)-2-propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
in 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is
stirred overnight at ambient temperature. The reaction is halted by
the addition of 2 ml of water and 0.5 ml of acetic acid, and then
extraction is carried out with ethyl acetate. The organic phases
are combined and dried over sodium sulfate. The solvents are
evaporated and then the residue is chromatographed on silica gel
(dichloromethane/methanol 90/10). 147 mg of
2-(S)-propyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid are obtained in the form of an oil. Yield=76%.
.sup.1H NMR (CDCl.sub.3, 400 MHz): 0.86 (t, J=7.1 Hz, 3H), 0.90 (t,
J=7.2 Hz, 3H), 1.24 (m, 8H), 1.43 (m, 2H), 1.61 (sext, J=7 Hz, 2H),
3.07-3.22 (m, 4H), 3.32 (s, 3H), 3.38 and 3.57 (2q, J=7.7 Hz, 2H),
4.13 (m, 1H), 4.41 (t, J=5.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.37
(d, J=8.4 Hz, 2H), 7.47-7.55 (m, 5H).
EXAMPLE 5
Synthesis of
2(S)-Benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid
a) 1.9 ml (16 mmol) of benzyl bromide are added to a mixture of 4.4
g (19 mmol) of silver oxide and 3.5 g (13 mmol) of methyl
(S)-3-(4-bromophenyl)-2-hydroxypropionate in 20 ml of diethyl
ether. The reaction mixture is stirred at 50.degree. C. for 12
hours. The mixture is filtered and then the solvents are
evaporated. The residue is chromatographed on silica gel
(heptane/ethyl acetate 80/20). 4 g of methyl
(S)-3-(4-bromophenyl)-2-benzyloxypropanoate are obtained in the
form of an oil. Yield=85%.
b) 635 mg (0.55 mmol) of tetrakis(triphenylphosphine)palladium are
added to a solution of 4 g (11 mmol) of methyl
(S)-3-(4-bromophenyl)-2-benzyloxypropionate and 4 g (17 mmol) of
methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine
in 25 ml of dimethylformamide. 10 ml of a 2M potassium phosphate
solution are added and the reaction mixture is stirred at
70.degree. C. for 1 hour. The reaction is halted by the addition of
50 ml of water and then extraction is carried out with ethyl
acetate. The organic phases are combined and dried over sodium
sulfate. The solvents are evaporated and then the residue is
chromatographed on silica gel (heptane/ethyl acetate 80/20). 2.6 g
of methyl
(S)-2-benzyloxy-3-[3'-(methylamino)biphenyl-4-yl]propanoate are
obtained in the form of an oil. Yield=61%.
c) 2.25 ml (13.9 mmol) of heptyl isocyanate are added to a solution
of 2.6 g (6.95 mmol) of methyl
(S)-2-benzyloxy-3-[3'-(methylamino)biphenyl-4-yl]propanoate in 15
ml of dichloromethane. The reaction mixture is stirred at ambient
temperature for 20 hours. The reaction is halted by the addition of
20 ml of water and then extraction is carried out with ethyl
acetate. The organic phases are combined and dried over sodium
sulfate. The solvents are evaporated and then the residue is
chromatographed on silica gel (heptane/ethyl acetate 70/30). 2.42 g
of methyl
(S)-2-benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
are obtained in the form of an oil. Yield=67%.
d) 16 mg (0.4 mmol) of sodium hydroxide are added to a solution of
70 mg (0.42 mmol) of methyl
(S)-2-benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
in 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is
stirred overnight at ambient temperature. The reaction is halted by
the addition of 2 ml of water and 0.5 ml of acetic acid, and then
extraction is carried out with ethyl acetate. The organic phases
are combined and dried over sodium sulfate. The solvents are
evaporated and then the residue is chromatographed on silica gel
(dichloromethane/methanol 90/10). 49 mg of
2(S)-benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid are obtained in the form of an oil. Yield=72%.
.sup.1H NMR (CDCl.sub.3, 400 MHz): 0.86 (t, J=7 Hz, 3H), 1.24 (m,
8H), 1.43 (m, 2H), 1.61 (sext, J=7 Hz, 2H), 3.10-3.26 (m, 4H), 3.33
(s, 3H), 4.24 (dd, J=4.4, 8 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.48
and 4.73 (2d, J=11.6 Hz, 2H), 7.21-7.30 (m, 6H), 7.37 (d, J=8.4 Hz,
2H), 7.47-7.55 (m, 5H).
EXAMPLE 6
Synthesis of
2(S)-Allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid
a) 100 mg of 10% palladium-on-charcoal are added to a solution of
2.4 g (4.66 mmol) of methyl
(S)-2-benzyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
in 10 ml of methanol. The reaction mixture is stirred overnight
under a hydrogen atmosphere. The reaction mixture is filtered and
then the solvents are evaporated. The residue is filtered through
silica gel (ethyl acetate). 1.61 g of methyl
(S)-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-hydroxypropionate
are collected in the form of a colorless oil. Yield=81%.
b) 58 .mu.l (0.70 mmol) of allyl bromide are added to a mixture of
162 mg (0.70 mmol) of silver oxide and 200 mg (0.47 mmol) of methyl
(S)-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-hydroxypropanoate
in 3 ml of diethyl ether. The reaction mixture is stirred at
40.degree. C. for 24 hours. The mixture is filtered and then the
solvents are evaporated. The residue is chromatographed on silica
gel (heptane/ethyl acetate 80/20 up to 60/40). 180 mg of methyl
(S)-2-allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
are obtained in the form of an oil. Yield=82%.
c) 56 mg (1.4 mmol, 3 eq) of sodium hydroxide are added to a
solution of 200 mg (0.47 mmol, 1 eq) of methyl
(S)-2-allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate
in 2 ml of 9/1 THF/methanol. The reaction mixture is stirred at
ambient temperature for 3 hours. The reaction is halted by the
addition of 2 ml of water and 0.5 ml of acetic acid, and then
extraction is carried out with ethyl acetate. The organic phases
are combined and dried over sodium sulfate. The solvents are
evaporated and then the residue is chromatographed on silica gel
(dichloromethane/methanol 90/10). 152 mg of
2(S)-allyloxy-3-[3'-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic
acid are obtained in the form of an oil. Yield=78%.
.sup.1H NMR (CDCl.sub.3, 400 MHz): 0.86 (t, J=6.8 Hz, 3H), 1.26 (m,
8H), 1.42 (m, 2H), 3.09-3.25 (m, 4H), 3.32 (s, 3H), 4.01 (dd,
J=5.8, 12.6 Hz, 1H), 4.16 (dd, J=5.7, 12.6 Hz, 1H), 4.22 (dd,
J=4.3, 7.6 Hz, 1H), 4.41 (t, J=5.6 Hz, 1H), 5.22 (d, J=10.4 Hz,
1H), 5.25 (d, J=18.8 Hz, 1H), 5.83 (m, 1H), 7.22 (d, J=7.6 Hz, 1H),
7.37 (d, J=8.4 Hz, 2H), 7.52 (m, 5H).
EXAMPLE 7
Crossed-Curve PPAR Transactivation Assay
Activation of the PPAR receptors by an agonist (activator) in HeLN
cells leads to the expression of a reporter gene, luciferase,
which, in the presence of a substrate, generates light. The
modulation of the PPAR receptors is measured by quantifying the
luminescence produced after incubation of the cells in the presence
of a reference agonist. The ligands will displace the agonist from
its site. The measurement of the activity is performed by
quantifying the light produced. This measurement makes it possible
to determine the modulatory activity of the compounds according to
the invention by the determination of the constant which is the
affinity of the molecule for the PPAR receptor. Since this value
can fluctuate depending on the basal activity and the expression of
the receptor, it is referred to as apparent Kd (KdApp in nM).
To determine this constant, "crossed curves" for the test product,
against a reference agonist, are prepared using a 96-well plate: 10
concentrations of the test product plus a concentration 0 are
arranged in a line, and 7 concentrations of the agonist plus a
concentration 0 are arranged in a column. This is 88 measurement
points for 1 product and 1 receptor. The remaining 8 wells are used
for repeatability controls.
In each well, the cells are in contact with a concentration of the
test product and a concentration of the reference agonist,
2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}phenylsulfanyl)-2-me-
thylpropionic acid for PPAR.alpha.,
{2-methyl-4-[4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-ylmethylsulf-
anyl]phenoxy}acetic acid for PPAR.delta. and
5-{4-[2-(methyl(pyrid-2-yl)amino)ethoxy]benzyl}thiazolidine-2,4-dione
for PPAR.gamma.. Measurements are also taken for total agonist
controls with the same products.
The HeLN cell lines used are stable transfectants containing the
plasmids ERE-.beta.Glob-Luc-SV-Neo (reporter gene) and PPAR
(.alpha., .delta., .gamma.) Gal-hPPAR. These cells are seeded in
96-well plates at the rate of 10 000 cells per well in 100 .mu.l of
DMEM medium without phenol red and supplemented with 10% of
defatted calf serum. The plates are then incubated for 16 hours at
37.degree. C. and 7% CO.sub.2.
The various dilutions of the test products and of the reference
ligand are added at the rate of 5 .mu.l per well. The plates are
subsequently incubated for 18 hours at 37.degree. C. and 7%
CO.sub.2. The culture medium is removed by turning over and 100
.mu.l of a 1:1 PBS/luciferin mixture are added to each well. After
5 minutes, the plates are read using the luminescence reader.
These crossed curves make it possible to determine the AC50 values
(concentration at which 50% activation is observed) of the
reference ligand at various concentrations of test product. These
AC50 values are used to calculate the Schild regression by plotting
a straight line corresponding to the Schild equation ("Quantitation
in Receptor Pharmacology", Terry P. Kenakin, Receptors and
Channels, 2001, 7, 371-385) which allows the KdApp values (in nM)
to be obtained.
Transactivation Results:
TABLE-US-00001 PPAR.alpha. PPAR.delta. PPAR.gamma. KdApp KdApp
KdApp Compounds (in nM) (in nM) (in nm) Reference 1:
2-(4-{2-[3-(2,4- 200 n.a. n.a. difluorophenyl)-1-
heptylureido]ethyl}phenylsulfany)- 2-methyl propionic acid
Reference 2: {2-methyl-4-[4- n.a. 10 n.a. methyl-2-(4-
(trifluoromethyl)phenyl)thiazol-5- ylmethylsulfanyl]phenoxy}acetic
acid Reference 3: 5-{4-[2- n.a. n.a. 30 (methyl(pyridin-2-
yl)amino)ethoxy]benzyl}thiazolidine- 2,4-dione Example 1:
2(S)-ethoxy-3-[3'-(3- 30 250 <1 heptyl-1-methylureido)biphenyl-
4-yl]propionic acid Example 2: 2(S)-ethoxy-3-[3'-(1- 250 2000 0.03
methyl-3-penylureido)biphenyl-4- yl]propionic acid Example 4:
2-(S)-propyloxy-3-[3'- 30 500 0.025 (3-heptyl-1-
methylureido)biphenyl-4- yl]propionic acid Example 5:
2-(S)-benzyloxy-3- 250 n.a. 0.03 [3'-(3-heptyl-1-
methylureido)biphenyl-4- yl]propionic acid Example 6:
2-(S)-allyloxy-3-[3'- 2 50 0.003 (3-heptyl-1-
methylureido)biphenyl-4- yl]propionic acid n.a. means not
active
TABLE-US-00002 TABLE 1 Compounds according to the present invention
##STR00017## Substituent as denoted in the present document KdApp
in nM Compounds according to Patent FR 2 812 876 ##STR00018##
Substituent as denoted in Patent FR 2 812 876 KdApp in nM Example 1
R1 = <1 Example 13 R10 = 500 2(S)-Ethoxy-3-[3'-(3-
CH.sub.2CH.sub.3 (S)-2-Ethoxy-3-(3'- CH.sub.2CH.sub- .3 heptyl-1-
{[methyl(1- methylureido)biphenyl- phenylmethanoyl) 4-yl]propionic
acid amino]methyl} biphenyl-4- yl)propionic acid Example 2 R2 =
0.03 Example 22 R4 = C(CH.sub.3).sub.3 250 2(S)-Ethoxy-3-[3'-(1-
(CH.sub.2).sub.4CH.sub.3 N-[4'-(2,4- methyl-3- Dioxothiazolidin-5-
pentylureido)biphenyl- ylmethyl)biphenyl- 4-yl]propionic acid
3-ylmethyl]-2,2,N- trimethyl- propionamide Example 1 R2 = <1
Example 35 R4 = 1000 2(S)-Ethoxy-3-[3'-(3- (CH.sub.2).sub.6CH.sub.3
N-[4'-(2,4- (CH.sub.2).sub- .5CH.sub.3 heptyl-1-
Dioxothiazolidin-5- methylureido)biphenyl- ylmethyl)biphenyl-
4-yl]propionic acid 3-ylmethyl]-N- methylheptanamide Example 4 R2 =
0.025 Example 23 R4 = 2000 2(S)-propyloxy-3-[3'-
(CH.sub.2).sub.6CH.sub.3 N-Octyl-4'-(2,4- (CH.sub.2-
).sub.7CH.sub.3 (3-heptyl-1- dioxothiazolidin-5-
methylureido)biphenyl- ylmethyl)biphenyl- 4-yl]propionic acid
3-carboxamide Example 5 R2 = 0.03 Example 32 R4 = 250
2(S)-benzyloxy-3-[3'- (CH.sub.2).sub.6CH.sub.3 N-[4'-(2,4-
(CH.sub.2).sub- .8CH.sub.3 (3-heptyl-1- Dioxothiazolidin-5-
methylureido)biphenyl- ylmethyl)biphenyl- 4-yl]propionic acid
3-ylmethyl]-N- methyldecanamide
These results show the affinity of the compounds for PPAR.gamma.
and more particularly the specificity of the affinity of the
compounds of the invention for the PPAR.gamma. subtype, compared
with the affinity of the compounds for the PPAR.alpha. subtype or
for the PPAR.delta. subtype.
EXAMPLE 8
Compositions
Various specific formulations based on the compounds according to
the invention are illustrated in this example.
A--Oral Route:
(a) 0.2 g Tablet:
TABLE-US-00003 Compound of Example 1 0.001 g Starch 0.114 g
Dicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc
0.010 g Magnesium stearate 0.005 g
(b) Suspension to be Taken Orally in 5 ml Vials:
TABLE-US-00004 Compound of Example 5 0.001 g Glycerol 0.500 g 70%
Sorbitol 0.500 g Sodium saccharinate 0.010 g Methyl
para-hydroxybenzoate 0.040 g Flavoring q.s. Purified water q.s. for
5 ml
(c) 0.8 g Tablet:
TABLE-US-00005 Compound of Example 2 0.500 g Pregelatinized starch
0.100 g Microcrystalline cellulose 0.115 g Lactose 0.075 g
Magnesium stearate 0.010 g
(d) Suspension to be Taken Orally in 10 ml Vials:
TABLE-US-00006 Compound of Example 4 0.200 g Glycerol 1.000 g 70%
Sorbitol 1.000 g Sodium saccharinate 0.010 g Methyl
para-hydroxybenzoate 0.080 g Flavoring q.s. Purified water q.s. for
10 ml
B--Topical Route:
(a) Salve:
TABLE-US-00007 Compound of Example 6 0.020 g Isopropyl myristate
81.700 g Liquid petrolatum 9.100 g Silica ("Aerosil 200", marketed
by Degussa) 9.180 g
(b) Salve:
TABLE-US-00008 Compound of Example 2 0.300 g White petrolatum, q.s.
for 100 g pharmaceutical grade
(c) Nonionic Water-in-Oil Cream:
TABLE-US-00009 Compound of Example 1 0.100 g Mixture of emulsive
lanolin 39.900 g alcohols, of waxes and of oils ("Anhydrous
eucerin", marketed by BDF) Methyl para-hydroxybenzoate 0.075 g
Propyl para-hydroxybenzoate 0.075 g Sterile demineralized water
q.s. for 100 g
(d) Lotion:
TABLE-US-00010 Compound of Example 3 0.100 g Polyethylene glycol
(PEG) 400 69.900 g 95% Ethanol 30.000 g
(e) Hydrophobic Salve:
TABLE-US-00011 Compound of Example 5 0.300 g Isopropyl myristate
36.400 g Silicone oil ("Rhodorsil 47 V 300", 36.400 g marketed by
Rhone-Poulenc) Beeswax 13.600 g Silicone oil ("Abil 300,000 cSt",
q.s. for 100 g marketed by Goldschmidt)
(f) Nonionic Oil-in-Water Cream:
TABLE-US-00012 Compound of Example 2 1.000 g Cetyl alcohol 4.000 g
Glyceryl monostearate 2.500 g PEG 50 stearate 2.500 g Shea butter
9.200 g Propylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075
g Propyl para-hydroxybenzoate 0.075 g Sterile demineralized water
q.s. for 100 g
Each patent, patent application, publication, text and literature
article/report cited or indicated herein is hereby expressly
incorporated by reference.
While the invention has been described in terms of various specific
and preferred embodiments, the skilled artisan will appreciate that
various modifications, substitutions, omissions, and changes may be
made without departing from the spirit thereof. Accordingly, it is
intended that the scope of the present invention be limited solely
by the scope of the following claims, including equivalents
thereof.
* * * * *